The objective of this Program Project is to unite a network of scientific investigators who are focusing on the molecular biology of the cell cycle in order to understand the mechanisms of oral carcinogenesis. This proposal consists of six highly interdependent research projects and cores, connected both scientifically and technically. The central theme uniting the three research projects is the perturbation of key cell cycle regulators in the genesis of oral cancer. These key regulators as well as a novel cell cycle regulator have been identified by this research group. Findings from the research projects will be validated by collaborative efforts of the Cell Culture Core and the Tissue Bank and Pathology Core. This program project will support and promote synergistic interactions among the cores and research projects that will speed up the investigations of the process central to the development of oral cancer: cell cycle control. There are three research projects in this oral cancer program project: "HPV and Cell Cycle Dysregulation in Oral Cancer" will study the role of human papillomavirus (HPV), the p53 and pRB pathways, and the cell cycle regulator cdk6 in oral cancer. "Cyclin D1 and a Genetic Model of Oral Carcinogenesis" will investigate the genetic basis of proliferation and transformation of oral keratinocytes by the aberrant expression of the G1- specific cyclin D1 oncogene in a transgenic mouse model. "Cell cycle Biology of doc-1" tests a putative tumor suppressor gene doc-1 as a regulator of the cell cycle. Three Core Facilities have been created to support the scientific projects. The Administrative Core, in addition to its managerial function, serves the important role of facilitating electronic communication and data sharing among the investigators. The tissue Bank and Pathology Core will collect and bank human oral tumors, and will create a database to compile clinical histories, provide tissues for culturing, and perform HPV typing, in situ hybridization, and immunohistochemistry. The Cell Culture Core will generate cell cultures from normal, premalignant, and malignant human and mouse oral biopsy specimens and will construct sable transductants for the research projects. These Cores will also validate conclusions from the research projects in human oral cancer tissues.